CN106176745A - Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, their preparation and their treatment use - Google Patents

Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, their preparation and their treatment use Download PDF

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Publication number
CN106176745A
CN106176745A CN201610569660.0A CN201610569660A CN106176745A CN 106176745 A CN106176745 A CN 106176745A CN 201610569660 A CN201610569660 A CN 201610569660A CN 106176745 A CN106176745 A CN 106176745A
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China
Prior art keywords
irbesartan
tablet
amlodipine
amlodipine besylate
besylate tablet
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Inventor
P.库拉
V.科尔
A.库尔卡尼
S.帕特尔
Y.法德克
D.萨拉瓦南
M.辛格特
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Sanofi SA
Sanofi Aventis France
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Sanofi Aventis France
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

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  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to comprise the stabilization of solid Pharmaceutical composition of the fixed dosage of irbesartan, Amlodipine Besylate Tablet and pharmaceutical excipient, their preparation and their treatment use.It is desirable to provide stable and bioequivalent with corresponding independent assortment irbesartan and the fixed Combination solid dosage of Amlodipine Besylate Tablet, at least partly alleviate amlodipine uniformity in the blend adding lubricant.The present invention relates to the stable oral medicine solid composite of the fixed dosage of monolayer tablet form, it comprises irbesartan, Amlodipine Besylate Tablet and pharmaceutical excipient, and wherein said irbesartan and described Amlodipine Besylate Tablet are that be physically separated and wherein coated granule form irbesartan is embedded in the extragranular matrix comprising Amlodipine Besylate Tablet.Irbesartan and Amlodipine Besylate Tablet can be used for preparation for the medicine treating hypertension.

Description

Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, it Preparation and their treatment use
The application is China's Application No. 200980161174.3, invention entitled " comprises irbesartan and amlodipine The solid pharmaceutical composition of fixed dosage, their preparation and their treatment use " and filing date JIUYUE in 2009 17 days The divisional application of patent application (PCT Application No. is PCT/IB2009/007027).
Technical field
The present invention relates to comprise irbesartan (irbesartan), Amlodipine Besylate Tablet (amlodipine And stable pharmaceutical solid composite (the solid stable of fixed dosage of pharmaceutical excipient besilate) Pharmaceutical fixed dose composition), their preparation and their treatment use.
Background technology
Such as USP 4,572,909 and USP 4, disclosed in 879,303, amlodipine for be used for treating hypertension and other Medical indications and the calcium channel blocker developed.Its chemical name is (+-)-2-[(2-amino ethoxy) methyl]-4- (2-chlorphenyl)-1,4-dihydro-6-picoline-3,5-dicarboxylic acids 3-ethyl 5-methyl ester.
Amlodipine is with trade nameOrSelling, it is single benzene sulfonate i.e. benzenesulfonic acid ammonia chlorine ground Flat.It can be applied with the intensity (strength) of 2.5mg, 5mg and 10mg as oral tablet.Non-in tablet Active component includes microcrystalline Cellulose, calcium phosphate dibasic anhydrous, primojel and magnesium stearate.
Amlodipine Besylate Tablet slightly soluble there is the absolute bioavailability of 64-90% in water.
Irbesartan is described in the United States Patent (USP) 5 of Bernhart et al., and in 270,317, by 5,270,317 are expressly incorporated herein work For reference.
Irbesartan is effective long-acting angiotensin ii receptor antagonist, and it is in treatment cardiovascular disease such as hypertension Particularly useful with in heart failure.Its chemical name is that [(2'-(tetrazolium-5-base) joins 2-normal-butyl-4-spiro cyclopentane-l- Benzene-4-base) methyl]-2-imidazoline-5-ketone.
Irbesartan is with trade nameOrSell.
Irbesartan is insoluble in water.Irbesartan has the distribution of parabolic type pH dissolubility in an aqueous medium, at pH There is between 2.0 and 6.0 minimal solubility and in 0.1N HCl and pH 7.5 phosphate buffer, there is maxima solubility.
It is frequently desirable to various active composition is incorporated in single medicine compositions.Multiple components is included in single combination There is provided for thing generally reduces cost and symptom individual for treatment and take in single medicine rather than the facility of multi-medicament.
But, the combination of active component is not without shortcoming.
Some physical property (particularly stability) of medicine is suitable to prepare the total impurities level with reduction in exploitation The preparation of tablet constitutes challenge to long-time stability.
Such as, irbesartan is floc, has relatively low bulk density and tap density.It is also viscosity and mill Damage property (abrasive) material.
These character make it difficult to the medicine ordinance of effective dose becomes to have uniform weight, hardness and other preferable tablet The tabloid of matter.It addition, irbesartan has a flow performance that some is undesirable, such as, its be viscosity and can adhere to On face, surface such as tablet punch (punch face) and die head, thus (especially enterprising at high speed tablet press in tableting processes In the tableting processes of row) cause problem.
The low-down water solublity of irbesartan also constitutes challenge, and this is owing to only can add limited amount excipient to promote Moistening, disintegrate and final drug release the most quickly and completely.
(it is also the fluffy of the mobility gone on business of performance and low aqueous solubility to add the second active component such as Amlodipine Besylate Tablet Pine material) such as tabletting or the problem of dosage unit uniformity can be further resulted in.
It addition, the stability of compositions can be lived with necessary excipient or even active component and second due to active component Property composition itself incompatible and compromise.
About the preparation containing only Amlodipine Besylate Tablet, it is very hygroscopic that WO2006/059217 discloses amlodipine And absorbing dampness, this causes decomposing.One of main path decomposed is through catalytic oxidation process, and this process is that pH is dependent. One of main decomposition products known in the art for 2-[(2-amino ethoxy) methyl]-4-(2-chlorphenyl)-6-picoline- 3,5-dicarboxylic acids 3-ethyl 5-methyl ester and its be referred to as impurity D.
WO2003/051364 discloses the stability of active component and obtains improving and contained microcrystalline Cellulose, lubricant With the Benzenesulfonate amlodipine tablet of disintegrating agent weight reduction and the preparation method of described tablet.
WO2008/062435 discloses the stabilization of solid dosage form of Amlodipine Besylate Tablet, its comprise polyhydric alcohol and Stably there is the total impurities level especially impurity D of reduction.
About the preparation containing irbesartan, the EP747050 of Sanofi discloses the pharmaceutical composition of tablet form, its Comprise single irbesartan or irbesartan and diuretic compound such as hydrochlorothiazide (hydrochlorothiazide) (HCTZ) Combination, preparation method includes: in the presence of lactose and antiplastering aid such as silicon dioxide, by outer for granule compositions (extragranular composition) with comprise single irbesartan or the granule that comprises two kinds of active component mixes. Stability problem does not occurs.
The WO2005/070762 of Sepracor discloses the oral formulations of capsule form, and it comprises S-amlodipine and strategic point The combination of Bei Shatan, obtains: in the following manner by the two of about 25wt% in the presence of corn starch and about 65wt% lactose Plant active component to be simply mixed together.Stability problem does not occurs.
Therefore, do not exist known to comprise irbesartan and Amlodipine Besylate Tablet the stabilization of solid dosage of particular combination Form.
Except stability, when preparing the solid compositions of fixed dosage, it is therefore an objective to offer facilitates the active component of patient Unitized dose form, this unitized dose form is raw with the corresponding independent assortment (free-combination) of identical active component Thing is of equal value.
" combination of fixed dosage or FDC " used in this application refers in single dose unit such as tablet or oral dose shape Two kinds of medicines or the combination of active component present in formula.
It addition, still as two kinds of medicines of two kinds of dosage unit administration while that " independent assortment " used in this application referring to Or the combination of active component.
Due to the biopharmaceutical properties of these complexity, exploitation and irbesartan and the independent assortment of Amlodipine Besylate Tablet The fixed Combination dosage form of bioequivalent irbesartan and Amlodipine Besylate Tablet arouses people's interest.
As a result, it is desirable to stable and bioequivalent with corresponding independent assortment irbesartan and Amlodipine Besylate Tablet Fixed Combination solid dosage.
Another challenge faced is when amlodipine accounts for the content of total tablet weight compared with the irbesartan of high-load Time the lowest, amlodipine uniformity in adding the blend of lubricant (lubricated blend).
The present invention seeks at least partly to alleviate disadvantages mentioned above.
Summary of the invention
This purpose is to be administered orally with the stable of the fixed dosage comprising irbesartan, Amlodipine Besylate Tablet and pharmaceutical excipient Medicinal solid compositions realizes, and wherein irbesartan and Amlodipine Besylate Tablet are physically separated.
Owing to Amlodipine Besylate Tablet does not suffers from decomposition and this combination product when carrying out studying (stress Study) show time and in final packaging that reduce and controlled impurity (even below same dose referring solely to product Impurity), the most this Solid Dosage Forms is advantageous particularly.
It addition, compared with every kind of active component single dissolution distribution, both irbesartan and Amlodipine Besylate Tablet Dissolution distribution is not compromised.
In a preferred embodiment, the irbesartan of coated granule form is embedded in comprises Amlodipine Besylate Tablet Extragranular matrix (extragranular matrix) in.
Preferably, solid composite of the present invention takes the form of monolayer tablet, the tablet form of preferred film coating.
Preferably, described tablet is packaged in suitable packaging material such as PVC, PVC/PVdC, PVC/PE/PVdC further In.
In a preferred embodiment of the present composition, irbesartan accounts for about the 20% of composition total weight to about 70%.
In a preferred embodiment of the present composition, Amlodipine Besylate Tablet accounts for the pact of composition total weight 1% to about 20%.
In a preferred embodiment of the present composition, pharmaceutical excipient is selected from diluent, disintegrating agent, anti-stick Agent, binding agent, lubricant and their mixture.
Preferably, described solid composite does not contains lactose.
In a preferred embodiment of the present composition, in the gross weight of tablet, the amount of irbesartan constitutes 150mg to 300mg, preferably 300mg or 150mg.
In a preferred embodiment of the present composition, the amount structure of Amlodipine Besylate Tablet in the gross weight of tablet Become 5mg to 10mg, preferably 7mg or 14mg.
In a preferred embodiment of the present composition, solid composite is tablet form, wherein tablet total weight Amount is 400mg to 600mg, preferably 500mg.
In a preferred embodiment, described compositions after 40 DEG C/75% relative humidity 6 months with regard to amlodipine Speech has the total impurities less than 1.50% (w/w) and has the total impurities less than 0.50% (w/w) for irbesartan.
According to another object, the present invention relates to prepare the stable oral pharmaceutical comprising irbesartan and Amlodipine Besylate Tablet The method of compositions, the method comprise the steps that
I. with the aqueous solution containing binding agent, irbesartan and one or more pharmaceutical excipients are pelletized, thus shape Become granule,
Ii. described granule it is dried；
The most individually, Amlodipine Besylate Tablet is blended with pharmaceutical excipient,
Iv. by irbesartan granule and step iii of step ii) Amlodipine Besylate Tablet blend mix；
The most optionally lubricating step iv after pre-lubrication step) mixture；And
Vi. mixture is pressed into tablet.
Preferably, at step i and the iii of described method) in the pharmaceutical excipient group that uses without lactose.
In a preferred embodiment, described method is further comprising the steps of: is coated tablet and is packaged in conjunction In suitable packaging material such as PVC, PVC/PVdC, PVC/PE/PVdC.
Preferably, pre-lubrication step is included in 10-25 minute implemented before lubricating step, preferably mixed in 20 minutes Close the mixture of step (iv).
According to another object, the present invention relates to irbesartan and Amlodipine Besylate Tablet in preparation for treating hypertension Purposes in medicine, wherein said medicine is the stabilization of solid composition forms of fixed dosage as above.
Preferably, described purposes refers to the second line treatment for hyperpietic, wherein uses amlodipine to lead to as calcium Road blocker (CCB) monotherapy or use irbesartan are not enough to control as angiotensin ii receptor antagonist (ARB) Described hyperpietic.
Accompanying drawing explanation
Fig. 1 shows irbesartan dissolution distribution in conventional media i.e. 0.1N HCl.
Fig. 2 shows amlodipine dissolution distribution in conventional media i.e. 0.1N HCl.
Detailed description of the invention
Irbesartan and the preferred composition of Amlodipine Besylate Tablet.
Both active component exist with single unit dosage form, such as tablet or pill, wherein irbesartan and benzene sulphur Acid amlodipine is physically separated.
The medical additive being suitable to be used together with Amlodipine Besylate Tablet in the present invention is selected from suitable diluent such as Microcrystalline Cellulose, dicalcium phosphate and proper lubrication agent such as magnesium stearate.
The medical additive being suitable to be used together with irbesartan in the present invention is fine selected from suitable diluent such as crystallite Tie up fluidizer such as silicon dioxide plain, suitable, proper lubrication agent such as magnesium stearate, suitable binding agent such as hypromellose Element.
In the present compositions, the composition of amlodipine part is similar to amlodipine formulationGinseng Composition according to composition and irbesartan part is similar toWith reference to composition (except for the difference that without lactose one water Compound).
In a preferred embodiment, described compositions does not contains lactose as diluent.It practice, this excipient Disappearance allows to realize optimum at Amlodipine Besylate Tablet global stability (global stability) aspect, especially drops The low amount of impurity D.
In the preferred form of tablet, irbesartan comprises the granule of Amlodipine Besylate Tablet and excipient to be embedded in Coated granule form in epimatrix exists.In order to promote preparation, by irbesartan with binding agent such as HPMC pelletize and by ammonia Flordipine is added on during extra-granular divides before the pressing step.
In another preferred form, irbesartan and amlodipine use the most suitably binding agent pelletize, so respectively It is blended with lubricant afterwards and suppresses further.
Therefore, solid composite takes the form of monolayer tablet, the tablet form of preferred film coating.
In another preferred form, the irbesartan granule and amlodipine granule that each contain excipient are passed through inertia Layer is separately.Solid composite thus takes the form of tri-layer tablets, the tablet form of preferred film coating.In this embodiment In, inert layer preferably comprises suitable diluent.
Preferred form is form of single sheet, and wherein physical barriers is positioned at around irbesartan active component.Physical barriers is used for Irbesartan (as shielded active component) is reduced or eliminated, and (another activity of described combination becomes with Amlodipine Besylate Tablet Point) between physical contact.
The preferred composition of the present invention contains one or more in the following component in shown concentration range (weight %): Irbesartan, 50-70%, most preferably 60%；Amlodipine Besylate Tablet, 1-10%, most preferably 2-6%；Diluent, 20-30%, Most preferably from about 25%；Binding agent, 1-5%, most preferably 2-3%；Disintegrating agent, 3-6%, most preferably from about 5%；Antiplastering aid/fluidizer, 0.25-5.0%, most preferably 0.7-2%；Lubricant, 0.5-1.5, most preferably from about 1%.
The amount of the every kind of composition (active component and additive) in solid dosage forms of the present invention can be clearly in following scope Interior variation.
The particle size distribution of irbesartan is important, because the fineness of irbesartan granule (fines) contributes to ammonia chlorine The uniformity of Horizon.The particle size distribution of irbesartan granule depends primarily in the fluid picked-up pelletized and in kneading time (fluid uptake).The preferred size of irbesartan granule be distributed in following in the range of: 65% to 85% pass through #60BSS, That is, size or diameter are less than 250 μm.
Observe for irbesartan of the present invention and amlodipine compound composition (formula composition) Whole pH is about 6.0, it is found that the pH referring solely to product is higher than 6.0, i.e. between pH 6.0 to 7.0.PH higher than 6 has It is beneficial to amlodipine compositions, but pH 6.0 times, the catabolic process of amlodipine accelerates.
Therefore, in the present invention, selected compositions can get pH 6 when being pressed into tablet.
Final primary packaging material (primary packaging material) used is blister package, i.e. impermeable Bright three layers (Opaque Triplex) (300micPVC/30micPE/90gsmPVdC) blister package, opaque bilayer (Opaque Duplex) (250micPVC and 60mic PVdC) blister package and aluminium foil (Alu-Alu) blister package.These materials will be avoided In amlodipine, the generation of impurity-D increases, and thus stops sunlight to be directly exposed to the sun on drug products.
The most controlled major impurity is impurity D, is referred to as 2-[(2-amino second in the art Epoxide) methyl]-4-(2-chlorphenyl)-6-picoline-3,5-carboxylic acid 3-ethyl 5-methyl ester.
In the compositions of the present invention, after 40 DEG C/75% relative humidity 6 months, find less than 1.5% for amlodipine (w/w) total impurities, but when irbesartan and amlodipine are not to be physically separated, find the impurity more than 1.6%. In a preferred embodiment, after 40 DEG C/75% relative humidity 6 months, in the compositions of the present invention, for amlodipine Find the total impurities less than 1.0% and more preferably less than 0.5% (w/w).
It addition, after 40 DEG C/75% relative humidity 6 months, in the compositions of the present invention, find to be less than for amlodipine The impurity D of 1.5% (w/w) [being actually 0.097%w/w], but when irbesartan and amlodipine are not to be physically separated Time, find impurity D more than 1.6%.In a preferred embodiment, after 40 DEG C/75% relative humidity 6 months, In the present composition, find the impurity D less than 1.0% and more preferably less than 0.15% (w/w) for amlodipine.
This explanation, the distribution of decomposing of particular composition P-TOLUENE SULFO ACID 99's amlodipine of the present invention has the impact of reduction.
On the other hand, after 40 DEG C/75% relative humidity 6 months, find less than 0.5% (w/w's) for irbesartan Total impurities.This explanation, the particular composition of the present invention is distributed not impact to the decomposition of irbesartan.It addition, the physics of tablet Character does not change such as color, shape, hardness and disintegration.
Physical property
Stability
In following condition combination of oral medication of the present invention is accelerated stability study: 40 DEG C/75% relative humidity RH, 30 DEG C/75% relative humidity and 25 DEG C/60% relative humidity.These are evaluated on the basis of following mensuration: when initial Between measure for irbesartan and Amlodipine Besylate Tablet between point and 6 months points In Vitro Dissolution, water capacity and relevant Material.
When irbesartan and amlodipine are to be physically separated, result provides total impurities water in amlodipine Flat (predominantly impurity D) significantly reduces.
Specifically find, in irbesartan is granulated the preparation being added on during extra-granular divides with amlodipine, ammonia chlorine The impurity level of Horizon is at a fairly low and in target limit.This compositions demonstrates more much lower than the impurity level with reference to product Impurity level.
Dissolving out capability
At multimedium the leaching condition such as acetate buffer of 0.1N HCl, pH 4.5, the phosphate-buffered of pH 6.8 In the phosphate buffer of liquid and pH 7.5, by " the dissolution of the tablet of the combination containing irbesartan and Amlodipine Besylate Tablet Performance " contrasted with reference to the dissolving out capability of product with every kind,.At initial time point and each time point between 60 minutes Monitoring dissolution progress.
Dissolution distribution refers to irbesartan or the percetage by weight of amlodipine release, based on E Beisha contained in tablet Smooth or the gross weight of amlodipine, it lasts dissolution in 60 minutes (for conventional media i.e. 0.1N under the conditions of different multimediums HCl, sees Fig. 1 and 2).
Result shows, irbesartan containing the present invention and the dissolving out capability of the tablet of the combination of Amlodipine Besylate Tablet with Comprise only the dissolving out capability equivalent of the tablet of every kind of active component i.e. irbesartan or amlodipine.
Preparation method
The method of the stable oral pharmaceutical composition that preparation comprises irbesartan and Amlodipine Besylate Tablet includes following step Rapid:
I. with the aqueous solution containing binding agent, irbesartan and one or more pharmaceutical excipients are pelletized, thus shape Become granule,
Preferably, acceptable excipient is selected from microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium.Preferably, acceptable Binding agent is selected from cellulose derivative such as hydroxypropyl methyl cellulose.
Ii. described granule it is dried；
The most individually, in order to make preferably being uniformly distributed of amlodipine, by Amlodipine Besylate Tablet and pharmaceutical excipient It is blended.Preferably, acceptable excipient is selected from microcrystalline Cellulose, silicon dioxide.
Iv. by irbesartan granule and step iii of step i)) Amlodipine Besylate Tablet blend mix；
The most optionally lubricating step iv after pre-lubrication step) mixture；With
Vi. mixture is pressed into tablet.
In a preferred embodiment of described method, pre-lubrication step was carried out before step v), it is therefore an objective to make strategic point Bei Shatan and amlodipine all realize excellent homogeneity.Preferably, before described pre-lubrication step is included in and is lubricated step 10-25 minute, preferably be lubricated before step 20 minutes blend step (iv) mixture.
It is true that due to irbesartan in granule, part exists and amlodipine and other extra-granular excipient such as Microcrystalline Cellulose and silicon dioxide mixing, therefore amlodipine being uniformly distributed in final blend is required.
Therefore, in granule, the suitably mixing of the outer material of material and granule is to obtain equal in final blend of amlodipine The important stage of even property, it can be implemented, directly by being mixed by outer to irbesartan granule and granule material in pre-lubrication step Content uniformity to amlodipine reaches the 90-110%, RSD (relative standard deviation) of labelled amount (label claim) and is less than 5% (this illustrates Amlodipine Besylate Tablet being uniformly distributed in the blend lubricated).
In a preferred embodiment, the pharmaceutical excipient group used in the process does not contains lactose.
Described method is further comprising the steps of: coated tablet is also packed, and is preferably packaged in opaque triple blister pack In dress.
Effectiveness performance
It is an object of the invention to the present composition containing irbesartan and Amlodipine Besylate Tablet use in preparation Purposes in the medicine for the treatment of hypertension, wherein said medicine is the stabilization of solid compositions shape of fixed dosage as above Formula.
In a preferred embodiment, deliver medicine to the present composition have slightly to the patient of moderate hypertension, As with amlodipine (calcium channel blocker CCB) or irbesartan (angiotensin ii receptor antagonist ARB) monotherapy It is not enough to the second line treatment of the hyperpietic controlled.
Devise III phase, double blinding, randomization, placebo, the partial factors experiment (partial of 8 weeks Factorial) to suffer from uncomplicated primary essential hypertension (uncomplicated primary essential Hypertension) at 8 weeks treatment post-evaluation irbesartan 150mg/ amlodipine 5mg tablet composition and irbesartan in patient 300mg/ amlodipine 5mg tablet composition, compares it with amlodipine 5mg, irbesartan 150mg and 300mg monotherapy Relatively.
This research is intended to prove, irbesartan and amlodipine 150/5mg or the anti-height of 300/5mg fixed dosage compositions Blood pressure effect is better than amlodipine or the effect of irbesartan monotherapy of corresponding dosage.
The present invention is described with reference to preferred embodiment.
But, within the scope of the present invention, many changes are possible.
Embodiment
Cl, C2, C3 represent Comparative formulation.I1, I2, I3 represent invention formulation, wherein irbesartan and amlodipine thing Rationality separates.
300mg or300mg represents formulation C 1, and it is the reference product of independent irbesartan.
Istin 10mg or10mg represents formulation C 2, and it is the reference product of independent Amlodipine Besylate Tablet Product.
Embodiment 1
Preparation compositions C3, wherein irbesartan is granulated together with amlodipine.
Table 1
Said preparation C3 can be prepared by any suitable method of granulating known in the art.
Embodiment 2
Preparing present composition I1, wherein irbesartan is in granule in part and amlodipine is added on granule Outward。
This combination is also referred to as test products.
Table 2
The outer granulating method of the irbesartan of tablet form and the combination of Amlodipine Besylate Tablet is prepared according to formula I1 (extragranulation process)。
Step-1: mixing irbesartan, crystallite fibre in Fastmixinggranulator (raped mixer granulator) Dimension element and cross-linked carboxymethyl cellulose sodium.
Step-2: the drying composite of step 1 is carried out pelletize with the aqueous solution of hypromellose.
Step-3: dry wet particle the granule with 1.00-2.00mm sieve mill-drying.
Step-4: add the outer material i.e. Amlodipine Besylate Tablet of granule, microcrystalline Cellulose and silicon dioxide and at low sheraing Blender mixes.
Step-5: magnesium stearate is added and mixes to the material of step 4 and in low sheraing blender.
Step-6: use suitable instrument to suppress the blend lubricated.
Step-7: be finally coated compressed tablets, to realize weight increase 2-4%.
Embodiment 3
Prepare present composition I2, wherein make irbesartan and Amlodipine Besylate Tablet thing by rationality by individually pelletizing Separate。
Table 3
Embodiment 4
The present composition I3 of preparation tri-layer tablets form, wherein makes irbesartan layer and benzenesulfonic acid ammonia by inert layer Flordipine layer is physically separated.
Table 4
Embodiment 5
Stability study
Combination of oral medication to the present invention is accelerated stability study under the following conditions: 40 DEG C/75% is relative Humidity RH, 30 DEG C/75% relative humidity and 25 DEG C/60% relative humidity.These are evaluated on the basis of following mensuration: just The In Vitro Dissolution measured for irbesartan and Amlodipine Besylate Tablet between beginning time point and 6 months points, water capacity and Related substances.
This test is carried out under the following conditions.
Tablet is packaged in opaque triple-aluminum blister package and this bubble-cap is packaged in carton box further, and According to ICH guide, carton box is carried out stability test, sample phase between each stability stage is taken out and is analyzed.
Stability result at+40 DEG C/75% relative humidity provides in table 5.
Table 5
The preparation cooperatively pelletized containing irbesartan and amlodipine grinds in the stability of 40 DEG C/75% relative humidity Demonstrate the impurity D of higher level in studying carefully when 2 months, therefore terminate further stability study.
From result above it can be inferred that, when irbesartan and amlodipine are when jointly pelletizing, total in amlodipine Impurity level improves and predominantly impurity D.
Finding when both irbesartan and amlodipine are to be physically separated, the impurity level in amlodipine is suitable Low.
Therefore, preparation I1 (wherein irbesartan be granulated and amlodipine is added on during extra-granular divides) demonstrates Good impurity level result, especially the most much lower than the impurity level with reference to product (Istin 10mg).
At present composition I1, in I2, I3, find few after 40 DEG C/75% relative humidity 6 months for amlodipine In the total impurities of 1.5% (w/w), when irbesartan and amlodipine are not to be physically separated, (C3) finds more than 1.6% Impurity.In a preferred embodiment, in the present composition (I1, I2, I3), 40 DEG C/75% relative humidity 6 The total impurities less than 1.0% and more preferably less than 0.5% (w/w) is found for amlodipine after Yue.
It addition, in the present composition (I1, I2, I3), after 40 DEG C/75% relative humidity 6 months, for ammonia chlorine ground The flat impurity D finding to be less than 1.5% (w/w), but when irbesartan and amlodipine are not to be physically separated, (C3) finds Impurity D more than 1.6%.In a preferred embodiment, in the present composition (I1, I2, I3), 40 DEG C/75% Relative humidity found the impurity D less than 1.0% and more preferably less than 0.15% (w/w) for amlodipine after 6 months.
In a further preferred embodiment, after 40 DEG C/75% relative humidity 6 months, at the present composition (I1), in, find the impurity D less than 0.15% (w/w) for amlodipine, and find less than 1.5% for amlodipine (w/w) total impurities.
This explanation, the distribution of decomposing of concrete compositions P-TOLUENE SULFO ACID 99's amlodipine of the present invention has the impact of reduction.
On the other hand, after 40 DEG C/75% relative humidity 6 months, find less than 0.5% (w/w) for irbesartan Total impurities.The concrete compositions of this explanation present invention is distributed not impact to the decomposition of irbesartan.
Embodiment 4
Bioequivalence dissolution is distributed
It is distributed the dissolution of product of the present invention to be distributed with the dissolution with reference to product and is contrasted.These researchs are according to as follows The multimedium dissolution distribution study condition established is implemented.
Dissolution distribution be carried out as follows: use Average tablet weight be 260mg [for 150/5mg and 150/10mg] or The irbesartan of 520mg [for 300/5 and 300/10mg intensity] and amlodipine FCT, use USP device II, put by tablet In 37 DEG C of 900ml dissolution mediums and measure irbesartan or amlodipine at different time point such as 10,15,30,45 and 60 Minute gradually amount [using HPLC, wavelength 240nm] of dissolution, until reaching 90% drug dissolution.
The result illustrated in fig 1 and 2 shows, the irbesartan containing the present invention and the sheet of Amlodipine Besylate Tablet combination The dissolving out capability of agent is equal with the dissolving out capability of the tablet individually containing every kind of active component irbesartan or amlodipine.
Embodiment 5
III phase clinical research
First research irbesartan and fixed Combination that is 150/5 of amlodipine and 300/5mg and with irbesartan 150 Carry out with 300mg.
The therapeutic alliance of expection irbesartan and amlodipine is being not enough to control with single irbesartan monotherapy Patient in the effect of enhancing is provided.
The irbesartan of the second research fixed Combination and amlodipine that is 150/5 and 150/10mg and with amlodipine 5 Carry out with 10mg.
The therapeutic alliance of expection irbesartan and amlodipine is being not enough to control with single irbesartan monotherapy Patient in the effect of enhancing is provided.
Result proves, in be not enough to the hyperpietic controlled by amlodipine 5mg monotherapy, by family's blood The irbesartan of fixed Combination and the resisting hypertension effect of amlodipine 150/5mg that pressure measurement (HBPM) is evaluated are better than independent ammonia The resisting hypertension effect of Flordipine 5mg.
By 244 patient randomization in each clinical research.This will provide 122 randomizations in each treatment group and suffer from Person and 103 patients for evaluation.
All treatments oral administration in the morning, once a day.
Effect standard
Carry out Home blood pressure BP measurement according to standard operation, use the most non-of identical empirical tests to invade for all patients Entering property BP monitor: every day twice, adheres to 7 days, 2 measured values and at night 2 measured values in the morning.
V2 (the 2nd visit is examined), V3 (the 3rd visit is examined) and V4 (the 4th is visited and examined) implements these HBPM phases in front one week.
Clinic BP measures and implements when visiting and examining every time.All Research Analysts use the automatic Noninvasive of identical empirical tests BP monitor.
Main efficacy standard (primary efficacy criterion): as the family SBP of main standard based on trouble Person is in the last measurement carried out for 7 days of each measurement phase.
The morning of first day of each measurement phase and the measurement in evening are taken the circumstances into consideration (discount) and are used in the standard, because will They are considered as training.
Main standard is based on all available measurements in most 24 measured values (every day, 4 measured values, continued 6 days) The meansigma methods of value calculates.As long as that works as each measurement phase have recorded minimum 12 correct measurement values for last 6 days, then calculate this and put down Average.
According to the first research, result proves (measuring (HBPM) by Home blood pressure to evaluate), after treatment 10 weeks (W10), The resisting hypertension effect of the irbesartan of fixed Combination/amlodipine 300/5mg is better than irbesartan 300mg monotherapy fall The resisting hypertension effect of lower shrinkage pressure (systolic blood pressure).
According to the second research, result proves (measuring (HBPM) by Home blood pressure to evaluate), mono-by amlodipine 5mg One therapy is not enough in the hyperpietic controlled, the irbesartan of fixed Combination and the resisting hypertension of amlodipine 150/5mg Effect is better than the resisting hypertension effect of single amlodipine 5mg.

Claims (16)

1. the stable oral medicine solid composite of the fixed dosage of monolayer tablet form, it comprises irbesartan, benzenesulfonic acid ammonia Flordipine and pharmaceutical excipient, wherein said irbesartan and described Amlodipine Besylate Tablet be physically separated and wherein The irbesartan of coated granule form is embedded in the extragranular matrix comprising Amlodipine Besylate Tablet.
2. the compositions of claim 1, wherein the described irbesartan granule of 65% to 85% have less than 250 μm size or Diameter.
3. the compositions of claim 1 or 2, wherein said tablet is film-coated.
4. the compositions any one of claims 1 to 3, wherein said irbesartan account for the 20% of described composition total weight to 70%.
5. the compositions any one of Claims 1-4, wherein said Amlodipine Besylate Tablet accounts for described composition total weight 1% to 20%.
6. the compositions any one of claim 1 to 5, wherein said pharmaceutical excipient is selected from diluent, disintegrating agent, anti-stick Agent, binding agent, lubricant and their mixture.
7. the compositions any one of claim 1 to 6, wherein said solid composite does not contains lactose.
8. the solid composite any one of claim 1 to 7, the amount structure of irbesartan described in the gross weight of wherein said tablet Become 150mg to 300mg, preferably 300mg or 150mg.
9. the solid composite any one of claim 1 to 8, Amlodipine Besylate Tablet described in the gross weight of wherein said tablet Constitute 5mg to 10mg, preferably 7mg or 14mg.
10. the solid composite any one of claim 1 to 9, it is tablet form, and the gross weight of wherein said tablet is 400mg to 600mg, preferably 500mg.
Compositions any one of 11. claim 1 to 10, it is after 40 DEG C/75% relative humidity 6 months, for ammonia chlorine Horizon has the total impurities less than 1.50% (w/w) and has the total impurities less than 0.50% (w/w) for irbesartan.
12. preparations comprise the side of the stable oral pharmaceutical composition of the monolayer tablet form of irbesartan and Amlodipine Besylate Tablet Method, the method comprise the steps that
I. with the aqueous solution containing binding agent, irbesartan and one or more pharmaceutical excipients are pelletized, thus formation Grain,
Ii. described granule it is dried；
The most individually, Amlodipine Besylate Tablet is blended with pharmaceutical excipient,
Iv. by irbesartan granule and step iii of step ii) Amlodipine Besylate Tablet blend mix；
V. optionally lubricating step iv after pre-lubrication step) mixture；And
Vi. described mixture is pressed into tablet.
The method of 13. claim 12, wherein at described method step i and iii) in use pharmaceutical excipient group without breast Sugar.
Method any one of 14. claim 12 to 13, wherein said pre-lubrication step is included in and carries out described lubricating step 10-25 minute before, preferably carry out before described lubricating step 20 minutes blend step (iv) mixture.
15. irbesartans and Amlodipine Besylate Tablet are used for the purposes treating in the medicine of hypertension, wherein said medicine in preparation Thing is the stabilization of solid composition forms of the fixed dosage any one of claim 1 to 11.
The purposes of 16. claim 15, its as with amlodipine as calcium channel blocker (CCB) monotherapy or with strategic point Bei Shatan is not enough to the second line treatment of the hyperpietic controlled as angiotensin ii receptor antagonist (ARB).
CN201610569660.0A 2009-06-30 2009-09-17 Comprise the solid pharmaceutical composition of the fixed dosage of irbesartan and amlodipine, their preparation and their treatment use Pending CN106176745A (en)

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